Novel prostamides for the treatment of glaucoma and related diseases

ABSTRACT

Disclosed herein are compositions comprising an amide related to a prostaglandin and a biogenic amine. Other aspects relate to certain chemical compounds, pharmaceutical compositions, and methods of treating glaucoma.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation application of U.S. application Ser. No.11/573,692, filed Jun. 12, 2007, which is a national stage applicationunder 35 U.S.C. §371 of PCT application PCT/US2005/035748, filed on Oct.4, 2005, which claims the benefit of provisional application No.60/616,780, filed on Oct. 6, 2004.

FIELD OF THE INVENTION

The present invention relates to novel amides related to prostaglandinsas potent ocular hypotensives that are particularly suited for themanagement of glaucoma and related diseases.

BACKGROUND OF THE INVENTION Description of Related Art

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage. Considering all types together,glaucoma occurs in about 2% of all persons over the age of 40 and may beasymptotic for years before progressing to rapid loss of vision. Certaineicosanoids and their derivatives have been reported to possess ocularhypotensive activity, and have been recommended for use in glaucomamanagement. Eicosanoids and derivatives include numerous biologicallyimportant compounds such as prostaglandins and their derivatives.Prostaglandins can be described as derivatives of prostanoic acid whichhave the structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandin F_(2α)(PGF_(2β))].

Prostaglandins were earlier regarded as potent ocular hypertensives,however, evidence accumulated in the last decade shows that someprostaglandins are highly effective ocular hypotensive agents, and areideally suited for the long-term medical management of glaucoma (see,for example, Bito, L. Z. Biological Protection with Prostaglandins,Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc., 1985, pp. 231-252;and Bito, L. Z., Applied Pharmacology in the Medical Treatment ofGlaucomas Drance, S. M. and Neufeld, A. H. eds., New York, Grune &Stratton, 1984, pp. 477-505. Such prostaglandins include PGF_(2α),PGF_(1α), PGE₂, and certain lipid-soluble esters, such as C₁ to C₂ alkylesters, e.g. 1-isopropyl ester, of such compounds.

Although the precise mechanism is not yet known experimental resultsindicate that the prostaglandin-induced reduction in intraocularpressure results from increased uveoscleral outflow [Nilsson et. al.,Invest. Ophthalmol. Vis. Sci. (suppl), 284 (1987)].

The isopropyl ester of PGF_(2α) has been shown to have significantlygreater hypotensive potency than the parent compound, presumably as aresult of its more effective penetration through the cornea. In 1987,this compound was described as “the most potent ocular hypotensive agentever reported” [see, for example, Bito, L. Z., Arch. Ophthalmol. 105,1036 (1987), and Siebold et al., Prodrug 5 3 (1989)].

Whereas prostaglandins appear to be devoid of significant intraocularside effects, ocular surface (conjunctival) hyperemia and foreign-bodysensation have been consistently associated with the topical ocular useof such compounds, in particular PGF_(2α) and its prodrugs, e.g., its1-isopropyl ester, in humans. The clinical potentials of prostaglandinsin the management of conditions associated with increased ocularpressure, e.g. glaucoma are greatly limited by these side effects.

U.S. Pat. No. 5,688,819, commonly assigned to Allergan, Inc., andincorporated herein by reference discloses compounds known asprostamides. Prostamides are distinguished from prostaglandins in thatthe oxygen which is bonded to carbonyl group is replaced by a nitrogenbearing substituent. Those skilled in the art will readily recognizethat this replacement significantly alters several electronic and stericproperties of an important structural feature in the biologicalmolecule. Significantly, it is commonly believed in the art thatresonance between the nitrogen lone pair and the carbonyl i-bond issignificantly greater than resonance between the carbonyl group and anoxygen lone pair in a carboxylic ester or a carboxylic acid. This beliefis supported by the well established experimental observation that thenitrogen atom in an amide is planar, as opposed to the pyramidalgeometry of an amine. Thus, the commonly accepted belief in the art isthat the nitrogen atom of an amine is sp³ hybridized, while nitrogenatom of an amide is sp² hybridized, with the bonded electrons occupyingthe sp² hybrid orbitals and the nonbonded electron pair occupying a porbital to allow for conjugation with the carbonyl r system. Bycontrast, the hybridization, bonding, and geometry of the electrons ofthe oxygen atom in water and alcohols are very similar to those ofcarboxylic acids or carboxylic esters.

The increased resonance between the nitrogen and the carbonyl group inthe amide confers several unique properties to the molecule. First, itis well known in the art that hydrolysis of amides is at least twoorders of magnitude slower than the hydrolysis of esters (see, forexample, Francis A. Carey, Organic Chemistry, New York: McGraw-Hill BookCompany, 1987, p. 779). Thus, hydrolysis of amides in vivo is slowed tosuch an extent that a prostamide cannot be considered to be a prodrug ofa prostaglandin. Second, the increased resonance significantly increasesthe barrier to rotation about the nitrogen-carbonyl sigma bond relativeto the analogous rotational barrier associated with esters andcarboxylic acids. Thus, a prostamide has a sterically significant,stable, rigid group replacing the oxygen atom of the prostaglandin. Thissignificant steric difference will have a significant effect in bindingto a number of receptor sites since geometry is important for manyreceptor sites. Since the carboxylic acid group of a prostaglandin is apolar, ionizable, group, with four potential hydrogen bond receivingelectron pairs, and in the case of the protonated acid, one potentialhydrogen bond donor, it is reasonable for a person of ordinary skill inthe art to believe that this functional group will be important to thebinding of the molecule to a number of receptors. It follows thatchanging the resonance properties, the hybridization of the bonding andnonbonding electrons, the geometry of the nitrogen atom, the number ofavailable hydrogen bonding sites, and the electronegativity of the ofthe nitrogen relative to oxygen, will confer significantly differentbiological properties to prostamides relative to prostaglandins.

Recently, it is becoming more commonly accepted in the art that amideshave distinct properties over carboxylic acids. For example, it has beenshown that anandamide, a common amide of arachidonic acid, hassignificant biological activity that arachidonic acid does not. Otherwork has also been done to show that amides have distinct activity ascompared to carboxylic acid, which has caused some in the field toclassify fatty acid amides as “a new family of biologically activelipids” (Bezuglov, et. al., “Synthesis and Biological Evaluation ofNovel Amides of Polyunsaturated Fatty Acids with Dopamine”, Bioorganic &Medicinal Chemistry Letters 11 (2001), 447-449).

It has been shown that prostamides have pronounced effects on smoothmuscle and are potent ocular hypotensive agents. Additionally,prostamides cause significantly lower ocular surface hyperemia thanprostaglandins. One prostamide exemplary of the these effects isbimatoprost, which is marketed by Allergan, Inc. under the trade nameLumigan®, which has the structure shown in Formula I below.

SUMMARY OF THE INVENTION

Disclosed herein are compositions comprising an amide related to aprostaglandin and a biogenic amine.

Other embodiments relate to a compound comprising an amide related to aprostaglandin and a biogenic amine, wherein said compound is notnaturally occurring.

Ophthalmic compositions comprising a therapeutically active agent or aprodrug thereof are also disclosed herein. In these ophthalmiccompositions, said therapeutically active agent comprises an amidefunctional group, wherein selective hydrolysis of said amide functionalgroup of the therapeutically active agent produces one compound havingagonist activity at a prostaglandin receptor and, another compoundselected from the group consisting of cholinomimetics, antimuscarinics,adrenergics, dopaminergics, α-adrenoreceptor antagonists, β-adrenergicantagonists, monoamine oxidase inhibitors, histaminergics,serotonergics, and thyroid drugs. of serotonin and analogs thereof,dopamine and analogs thereof, and epinephrine and analogs thereof.

A method of treating glaucoma is also disclosed herein. This methodcomprises administering to a mammal suffering from glaucoma an effectiveamount of a therapeutically active agent or a pharmaceuticallyacceptable salt or a prodrug thereof. In this method, thetherapeutically active agent consists of a prostaglandin and a biogenicamine having 5 or more carbon atoms coupled by an amide bond.

DETAILED DESCRIPTION OF THE INVENTION

The term “prostaglandin” referred to herein should be interpretedbroadly as a natural prostaglandin, a prostaglandin analog, aprostaglandin receptor agonist, or a prodrug, a salt, or a salt of aprodrug of any of the previous three types of compounds. A naturalprostaglandin is defined as one of several prostaglandin compounds thatare produced in living organisms. The structural formula previouslydepicted is represented below in a modified form for clarificationpurposes to aid in understanding certain claim elements used herein.

In reference to the compounds related to this invention herein, the term“α chain” refers to the top chain which is formed by the carbon atomsreferred to as 1-7 in the structure above. The term “ω chain” refers tothe bottom chain which is formed by the carbon atoms referred to as13-20 in the structure above. The ring formed by the carbon atomsreferred to as 8-12 will be referred to as the “cyclopentyl ring” hereinfor convenience. The letters A, B, and E indicate carbons which haveparticular functional groups in the natural prostaglandins. A and B canbe either CHOH or C═O, depending upon the particular naturalprostaglandin, and E is CHOH where the OH is in the α-configuration(points downward). The dashed lines indicate where double bonds arepresent in certain of the natural prostaglandins.

Three classes of natural prostaglandins of particular interest hereinare prostaglandin E, prostaglandin F, and prostaglandin D. All of thecompounds known collectively as prostaglandin E are characterized by thecommon features that A is C═O and B is CHOH where the OH is in theα-configuration. One prostaglandin E which is of interest herein isprostaglandin E₁, which has a single covalent bond between carbons 5 and6 and a double covalent bond between carbons 13 and 14. Anotherprostaglandin E of interest herein is prostaglandin E₂, which has adouble covalent bond between carbons 5 and 6 and a double covalent bondbetween carbons 13 and 14. Thus, the subscript designates the number ofcarbon-carbon double bonds found in the basic prostaglandin structure.

The compounds known collectively as prostaglandin F are characterized bythe common features that both A and B are CHOH. Similar to prostaglandinE the OH is in the α-configuration for B, but the configuration of theOH of A is designated by a subscript. Thus, prostaglandin F_(2α), whichis of particular interest herein, is a prostaglandin F which has the OHof B in the α-configuration, and similar to prostaglandin E₂,prostaglandin F_(2α) has two double covalent carbon-carbon bonds betweencarbons 5 and 6 and carbons 13 and 14.

The compounds known collectively as prostaglandin D are characterized bythe common features that A is CHOH, where the OH is in theα-configuration, and B is C═O. Similar to the previous examples, oneprostaglandin D of interest herein is designated prostaglandin D₂, whichindicates that the compound has two double covalent carbon-carbon bondsbetween carbons 5 and 6 and carbons 13 and 14.

The term “analog” as used herein in relation to a biologically activemolecule refers to a compound having certain structural or biologicalsimilarities to said biologically active molecule. Specifically, ananalog should 1) act at a common receptor to the molecule in question,2) be structurally identical to the biologically active molecule withthe exception that the analog has one or more reasonable equivalents ofcertain groups or moieties in said biologically active molecule, 3) be acombination of said biologically active molecule and another moleculeacting at a common receptor, or 4) be a “combination” as cited abovehaving one or more reasonable equivalents of certain groups or moietiesin said combination.

A “combination” of molecules is applicable where two molecules have morethan one different feature, and is defined as a molecule having thecommon features of the two molecules and a combination of the featureswhich are different between the two molecules. Thus “combinations” of amolecule J-X—Y and a molecule K—X—Z would be K—X—Y and J-X—Z.

A reasonable equivalent to a feature is a feature that a person ofordinary skill in the art would reasonably consider as having a similarpurpose, but might enhance the properties of the compound. While notintending to limit the scope of the invention in any way, in general, anatom or functional group which is isovalent or isoelectronic with theatom or functional group it is replacing would be a reasonableequivalent. Thus, for example, an α-CHSH group is a reasonableequivalent for an α-CHOH group, and a C═S group is a reasonableequivalent for a C═O group. Another type of reasonable equivalent hasdifferent electronic properties but similar steric properties to thegroup it is replacing. Thus, F is a reasonable equivalent for H and OCH₃is a reasonable equivalent for OH.

If any knowledge exists relevant to the function of certain groups on aparticular chemical compound, this knowledge may be related to what isconsidered a reasonable equivalent. Thus, for example, if it is believedthat the electron-withdrawing properties of a particular group or moietyare important to the desired function of the molecule, a reasonableequivalent of said group might have equal or greaterelectron-withdrawing ability. Alternatively, if it is believed that theelectron-withdrawing properties of a group adversely affect theproperties of the molecule, a reasonable equivalent of said group mighthave a lower electron-withdrawing ability, or be electron-donating.Similar considerations can be made to other properties related tofunctional groups such as steric considerations, bond conjugation,aromaticity, electronegativity, hydrogen bonding, hydrophobicity, Vander Waals interactions, and other similar properties of functionalgroups known to affect the behavior of chemical compounds.

While not intending to limit the overall scope of the invention in anyway, certain types of analogs have specific meanings in relation to thecompounds, compositions, and methods disclosed herein. For example, aspecifically designated prostaglandin analog (e.g. “prostaglandin Fanalog”) has all of the features of that natural prostaglandin relatedto A, B, and E, including stereochemistry, and the presence or absenceof double bonds at carbons 5, 6, 13 and 14, or reasonable equivalents ofthose features. Beyond the similarities for A, B, E and the double bondsindicated, a specifically designated prostaglandin analog will have acyclopentyl ring, an α-chain, and an ω-chain which are attached toadjacent atoms on the cyclopentyl ring. The terms “cyclopentyl ring”, “αchain”, and “ω chain” have broader definitions for prostaglandin analogsthan they do for natural prostaglandins. For a prostaglandin analog, the“cyclopentyl ring” is a five-membered ring consisting of three or morecarbon atoms, the “α-chain” has between 4 and 12 carbon atoms and the“ω-chain” has between 4 and 20 carbon atoms. Either chain may comprisedouble or triple covalent bonds, aromatic or aliphatic rings, andheteroatoms such as S, O, N, and halogens. The only stereochemicalrequirements of prostaglandin analogs are the same as those of thenatural prostaglandins they are associated with. Thus, for aprostaglandin E analog, B and E should be CHOH with the OH in theα-configuration, and the α- and ω-chains should have the α and βconfigurations respectively with relation to the connection to thecyclopentyl ring. The table below lists features which would be presentin analogs of several types of natural prostaglandins. Alternatively, areasonable equivalent for each feature might be present in the givenprostaglandin analog.

Prosta- glandin Analog A B E C5-C6 C13-C14 E C═O CH(OH)α CH(OH)α NA NAconf conf E₁ C═O CH(OH)α CH(OH)α single bond trans double conf conf bondE₂ C═O CH(OH)α CH(OH)α cis double trans double conf conf bond bond FCH(OH) CH(OH)α CH(OH)α NA NA conf conf F_(2α) CH(OH)α CH(OH)α CH(OH)αcis double trans double conf conf conf bond bond D CH(OH)α C═O CH(OH)αNA NA conf conf D₂ CH(OH)α C═O CH(OH)α cis double trans double conf confbond bond NA means there is no requirement.

While these compounds are specifically understood to be analogs of theprostaglandins listed in the table above, other compounds that do notfall within the specific definition disclosed in this section, but whichare analogs of these or other prostaglandins according to the definitiongiven earlier, can be conceived by those of ordinary skill in the artand are considered to be within the scope of the relevant claims madeherein.

“A prostaglandin receptor agonist” refers to a compound which binds toand activates one of the prostaglandin receptors at a concentration ofless than 10⁴ nanomolar according to the Radioligand Binding and theFLIPR™ assay described hereafter. Of particular interest herein arecompounds having agonist activity at an FP receptor, an EP₁ receptor, anEP₂ receptor, an EP₄ receptor, and/or a DP receptor.

Radioligand Binding Cells Stably Expressing EP₁, EP₂, EP₄ and FPReceptors

HEK-293 cells stably expressing the human or feline FP receptor, or EP₁,EP₂, or EP₄ receptors were washed with TME buffer, scraped from thebottom of the flasks, and homogenized for 30 sec using a Brinkman PT10/35 polytron. TME buffer was added to achieve a final 40 ml volume inthe centrifuge tubes (the composition of TME is 100 mM TRIS base, 20 mMMgCl₂, 2M EDTA; 10 N HCl is added to achieve a pH of 7.4).

The cell homogenate was centrifuged at 19000 r.p.m. for 20 min at 4° C.using a Beckman Ti-60 rotor. The resultant pellet was resuspended in TMEbuffer to give a final 1 mg/ml protein concentration, as determined byBiorad assay. Radioligand binding competition assays vs. [³H-]17-phenylPGF_(2α) (5 nM) were performed in a 100 μl volume for 60 min. Bindingreactions were started by adding plasma membrane fraction. The reactionwas terminated by the addition of 4 ml ice-cold TRIS-HCl buffer andrapid filtration through glass fiber GF/B filters using a Brandel cellharvester. The filters were washed 3 times with ice-cold buffer and ovendried for one hour.

[³H-] PGE₂ (specific activity 180 Ci mmol) was used as the radioligandfor EP receptors. [³H] 17-phenyl PGF_(2α) was employed for FP receptorbinding studies. Binding studies employing EP₁, EP₂, EP₄ and FPreceptors were performed in duplicate in at least three separateexperiments. A 200 μl assay volume was used. Incubations were for 60 minat 25° C. and were terminated by the addition of 4 ml of ice-cold 50 mMTRIS-HCl, followed by rapid filtration through Whatman GF/B filters andthree additional 4 ml washes in a cell harvester (Brandel). Competitionstudies were performed using a final concentration of 5 nM [³H]-PGE₂, or5 nM [³H] 17-phenyl PGF_(2α) and non-specific binding determined with10⁻⁵M of unlabeled PGE₂, or 17-phenyl PGF_(2α) according to receptorsubtype studied.

Cells Transiently Expressing EP₃ Receptors

COS-7 cells were transiently transfected with pcDNA₃ containing cDNA forthe EP_(3D) receptor by employing lipofectin. For radioligand bindingthe cells were harvested after 2 days. Plasma membrane preparations foreach of the transient transfectants is as follows. COS-7 cells werewashed with TME buffer, scraped from the bottom of the flasks, andhomogenized for 30 sec using a Brinkman PT 10/35 polytron. TME bufferwas added to achieve a final 40 ml volume in the centrifuge tubes.

The cell homogenate was centrifuged at 19000 r.p.m. for 20 min at 4° C.using a Beckman Ti-60 rotor. The resultant pellet was resuspended in TMEbuffer to give a final 1 mg/ml protein concentration, as determined byBiorad assay. Radioligand binding assays were performed in a 200 μlvolume, as described above for other EP receptors.

Cells Transiently Expressing TP Receptors

COS-7 cells were transiently transfected with pcDNA₃ containing cDNA forthe TP receptor using methods as described for transient EP₃ receptortransfectants. Plasma membrane preparations for the transienttransfectants and radioligand binding methods were the same as for theEP₃ receptor methods. The binding of [³H]-SQ29548 (specific activity41.5 Ci mmol⁻¹) at TP receptors was determined in duplicate in at leastthree separate experiments. Incubations were for 60 min at 25° C. andwere terminated by the addition of 4 ml of ice-cold 50 mM TRIS-HCl,followed by rapid filtration through Whatman GF/B filters and threeadditional 4 ml washes in a cell harvester (Brandel). Competitionstudies were performed using a final concentration of 5 nM [³H]-SQ 29548and non-specific binding determined with 10⁻⁵ M of unlabeled SQ 29548.

Methods for FLIPR™ Studies (a) Cell Culture

HEK-293(EBNA) cells, stably expressing one type or subtype ofrecombinant human prostaglandin receptors (prostaglandin receptorsexpressed: hDP/Gqs5; hEP₁; hEP₂/Gqs5; hEP_(3A)/Gqi5; hEP₄/Gqs5; hFP;hIP; hTP), were cultured in 100 mm culture dishes in high-glucose DMEMmedium containing 10% fetal bovine serum, 2 mM 1-glutamine, 250 μg/mlgeneticin (G418) and 200 μg/ml hygromycin B as selection markers, and100 units/ml penicillin G, 100 μg/ml streptomycin and 0.25 μg/mlamphotericin B.

(b) Calcium Signal Studies on the FLIPR™

Cells were seeded at a density of 5×10⁴ cells per well in Biocoat®Poly-D-lysine-coated black-wall, clear-bottom 96-well plates(Becton-Dickinson) and allowed to attach overnight in an incubator at37° C. Cells were then washed two times with HBSS-HEPES buffer (HanksBalanced Salt Solution without bicarbonate and phenol red, 20 mM HEPES,pH 7.4) using a Denley Cellwash plate washer (Labsystems). After 45minutes of dye-loading in the dark, using the calcium-sensitive dyeFluo-4 AM at a final concentration of 2 μM, plates were washed fourtimes with HBSS-HEPES buffer to remove excess dye leaving 100 μl in eachwell. Plates were re-equilibrated to 37° C. for a few minutes.

Cells were excited with an Argon laser at 488 nm, and emission wasmeasured through a 510-570 nm bandwidth emission filter (FLIPR™,Molecular Devices, Sunnyvale, Calif.). Drug solution was added in a 50μl volume to each well to give the desired final concentration. The peakincrease in fluorescence intensity was recorded for each well. On eachplate, four wells each served as negative (HBSS-HEPES buffer) andpositive controls (standard agonists: BW245C (hDP); PGE₂ (hEP₁;hEP₂/Gqs5; hEP_(3A)/Gqi5; hEP₄/Gqs5); PGF_(2α) (hFP); carbacyclin (hIP);U-46619 (hTP), depending on receptor). The peak fluorescence change ineach drug-containing well was then expressed relative to the controls.

Compounds were tested in a high-throughput (HTS) orconcentration-response (CoRe) format. In the HTS format, forty-fourcompounds per plate were examined in duplicates at a concentration of10⁻⁵ M. To generate concentration-response curves, four compounds perplate were tested in duplicates in a concentration range between 10⁻⁵and 10⁻¹¹ M. The duplicate values were averaged. In either, HTS or CoReformat each compound was tested on at least 3 separate plates usingcells from different passages to give an n 3.

In addition to those aspects of prostaglandins discussed in theaforementioned disclosure, certain other features of particular interestin relation to the prostaglandins are contemplated herein. In certainuseful embodiments disclosed herein, the prostaglandin comprises from 0to 2 double covalent bonds connecting two carbon atoms. In otherembodiments, the prostaglandin comprises two double covalent bondsconnecting two carbon atoms. In other useful embodiments, theprostaglandin comprises from 1 to 3 heteroatoms, wherein saidheteroatoms comprise S or O, said heteroatoms replacing carbon atomswhich are present in prostaglandin E₂, prostaglandin F₂, orprostaglandin D₂. Of particular interest herein are compounds related toa prostaglandin comprising a moiety which replaces from 2 to 5 carbonatoms on the terminal end of a co chain of a natural prostaglandin, saidmoiety comprising phenyl, naphthyl, benzothienyl, furanyl, or thienyl.

The terms “FP-related”, “EP₁-related”, “EP₂-related”, “EP₄-related”, and“DP-related”, are generic terms used to classify prostaglandincompounds. The term “FP-related” refers to a compound which is an FPreceptor agonist, a prostaglandin F, a prostaglandin F analog, or a saltor prodrug of one of those compounds. Similarly, the term “EP₁-related”refers to a compound which is an EP₁ receptor agonist, a prostaglandinE, a prostaglandin E analog, or a salt or prodrug of one of thosecompounds. The term “EP₂-related” refers to a compound which is an EP₂receptor agonist, a prostaglandin E, a prostaglandin E analog, or a saltor prodrug of one of those compounds. The term “EP₄-related” refers to acompound which is an EP₄ receptor agonist, a prostaglandin E, aprostaglandin E analog, or a salt or prodrug of one of those compounds.The term “DP-related” refers to a compound which is an DP receptoragonist, a prostaglandin D, a prostaglandin D analog, or a salt orprodrug of one of those compounds.

The term “prodrug” used in relation to a natural prostaglandin, aprostaglandin analog, or a prostaglandin receptor agonist has themeaning normally understood in the art. That is, the prodrug is acompound which readily decomposes in vivo to form a naturalprostaglandin, a prostaglandin analog, or a prostaglandin receptoragonist. While not intending to limit the scope of the invention in anyway, one common type of prodrug is an ester which hydrolyzes to yield anactive compound with a hydroxyl functional group.

The term “salt” has the meaning normally understood by those of ordinaryskill in the art. A “pharmaceutically acceptable salt” is any salt thatretains the activity of the parent compound and does not impart anydeleterious or untoward effect on the subject to which it isadministered and in the context in which it is administered.

Pharmaceutically acceptable salts of acidic functional groups may berelated to organic or inorganic bases. The salt may be a mono orpolyvalent ion. Of particular interest are the inorganic ions, lithium,sodium, potassium, calcium, and magnesium. Organic salts may be madewith amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Hydrochloric acid or some otherpharmaceutically acceptable acid may form a salt with a compound thatincludes a basic group, such as an amine or a pyridine ring.

The definitions of the terms natural prostaglandin, prostaglandinanalog, a prostaglandin receptor agonist, prodrug, and salts givenherein are intended only to clarify the meaning of certain claimelements and are not intended to narrow in any way the overall scope ofthe claims taken as a whole.

The term “biogenic amine” as used herein refers to broadly an aminewhich elicits a physiological response in a mammal. This physiologicalresponse may be a detectable response of a particular group of cells,organs, or tissues in a living mammal; or may be detectable in vitro interms of binding, agonism, or antagonism of a particular receptor, orset of receptors, present in a mammal; or may be a response that isuseful in treating or preventing an undesirable condition or disease ina mammal. While not intending to limit the overall scope of theinvention in any way, examples of biogenic amines includecholinomimetics; antimuscarinics such as tropicamide; adrenergics suchas epinephrine and isoprotenenol; dopaminergics, including dopamine;α-adrenoreceptor antagonists such as phentolamine; β-adrenergicantagonists such as timolol, salbutanol and salmeterol; monoamineoxidase inhibitors such as trancylpromine; histaminergics such ashistamine and dimaprit; serotonergics, including dopamine and analogsthereof; thyroid drugs such as thyroxine; and analogs, prodrugs, andpharmaceutically acceptable salts of any of the above compounds or typesof compounds.

In certain embodiments, the biogenic amine is an amine selected from thegroup consisting of adrenergics, epinephrine, dopaminergics, dopamine,agonists of serotonin receptors, and serotonin. The term “amide” usedherein has the meaning normally understood by those of ordinary skill inthe art of organic chemistry, as a chemical compound having an amidefunctional group. An amide functional group, as understood by those ofordinary skill in the art, comprises a carbonyl (C═O) group where thecarbonyl carbon is directly bonded to a nitrogen atom related to anamine. This means that when the amide is formed, the carbon atom of thecarbonyl group replaces one of the hydrogen atoms of the amine, and thenitrogen of the amine replaces one of the moieties attached to thecarbonyl group.

The bond between the carbonyl carbon and the nitrogen atom related tothe amine is referred to as an “amide bond”. This description of theamide, the amide functional group, and the amide bond is purely a mentalexercise and is not meant to be necessarily related to how the amide isactually formed. Thus, the amide may be formed by a number means otherthan by the formation of an amide bond, such as by oxidation of anamine, and the amide bond may not have been formed at all, but maysimply exist because a compound is an amide.

The term “related to” used with reference to a prostaglandin and anamide refers to the fact that an amide bond is formed between the twousing the mental exercise just described, that is one of the moietiesattached to the carbonyl and one of the hydrogen atoms attached to theamine nitrogen are replaced with a direct bond between the carbonylcarbon and the nitrogen. As mentioned, the amide is a product of amental exercise, and the term “related to” should not be construed asmeaning that the compound is necessarily prepared from the prostaglandinand the amine or related compounds thereof. In fact, those skilled inthe art will recognize that an amide “related to” a prostaglandin and anamine may be prepared without forming either molecule. In addition, theterm “related to” refers to the fact that the amide might be a prodrugof the molecule that results from the formation of an amide bond betweenthe amine and the prostaglandin. The term “related to” also recognizesthat the prostaglandin may be a carboxylic acid, or an ester, or someother derivative of a carboxylic acid such as a nitrile. Thus, “relatedto” describes the prostaglandin and the amine related to the amide, andrecognizes that certain minor and easily reversible changes may havebeen made to certain oxygen, nitrogen, or sulfur containing functionalgroups, and that no change in the carbon-carbon bonding is made toeither the prostaglandin or the amine.

In reference to an amide functional group related to the present claims,the term “selective hydrolysis of said amide functional group” refers toa mental exercise wherein the amide functional group is hydrolyzed witha water molecule or a hydroxide ion to form a carboxylic acid, or a saltof a carboxylic acid, and an amine. It is not necessary that aparticular amide under consideration be capable of selective hydrolysisat the amide functional group since the hydrolysis is strictly a mentalexercise.

In general, analogs of the amines of interest herein are identifiedaccording to the definition given previously herein. However, while notintending to limit the overall scope of the invention in any way,certain types of molecules are specifically designated as analogs ofcertain amines of particular interest herein. These amines of particularinterest include serotonin, dopamine, and epinephrine. In the case ofthese amines, an analog is specifically designated to include having thesame basic structure as the parent, that is an aromatic ring linked to anitrogen atom by an ethylene moiety, but having one or two of thefollowing changes: 1) adding or subtracting one or two atoms ormethylene groups from the ethylene linker attaching the nitrogen to thearomatic ring, 2) substituting one or more oxygen atoms with sulfur, 3)substituting one or more hydrogen atoms with a fluorine, 4) adding 1-3additional substituents to the aromatic ring, 5) removing one or morehydroxyl moieties, 6) adding or removing a C₁₋₃ alkyl moiety to or fromthe nitrogen, and 7) changing an alkyl group on the nitrogen by addingor removing one or two carbon atoms and the associated hydrogen atoms.While these compounds are specifically identified as being analogs ofserotonin, dopamine, and epinephrine, other compounds that do not fallwithin the specific definition disclosed in the this paragraph, butwhich are analogs of these or other amines according to the definitiongiven earlier, can be conceived by those of ordinary skill in the artand are considered to be within the scope of the relevant claims madeherein.

Other embodiments relate to therapeutically active agents agentconsisting of a prostaglandin and a 2-aryl-1-ethylamine coupled by anamide bond. The term “2-aryl-1-ethylamine” used with respect to theseembodiments refers to a primary or secondary amine where the nitrogen ofthe amine is linked to an aromatic ring by an ethylene group. This meansthat the two groups are attached to opposite ends (different carbonatoms) of the ethylene group. Furthermore, the ethylene group and thearomatic ring may optionally have one or more hydroxyl or acyloxymoieties attached, where a hydrogen atom is replaced by a hydroxyl (OH)moiety. In certain embodiments, the 2-aryl-1-ethylamine comprises from 1to 3 hydroxy or acyloxy moieties.

The amides disclosed herein can be prepared by a number of methods wellknown in the art. While not intending to limit the scope of the claimsin any way, one convenient method of preparing these compounds is byreacting a prostaglandin having a carboxylic acid moiety with the aminein the presence of an appropriate catalyst and an appropriate base, toform the amide. While not intending to limit the scope of the inventionin any way, examples of useful procedures for preparing amides areprovided herein. In many cases, it is necessary to protect certainfunctional groups on the amine and prostaglandin in order to carry outthe amidation reaction. The use of protecting groups to accomplish thisobjective is well known in the art and well within the skill of one ofordinary skill in the art of organic chemistry, and an example of aprotection process is disclosed in one of the examples herein. Theamines and the prostaglandins of the present invention can be preparedby methods well known in the art, purchased, or in some cases, may beisolated from natural sources. For example, the following U.S. Patents,incorporated herein by reference, describe methods for preparing variousprostaglandin compounds: U.S. Pat. No. 6,586,462; U.S. Pat. No.6,538,018; U.S. Pat. No. 6,531,504; U.S. Pat. No. 6,410,591; U.S. Pat.No. 6,376,533; and U.S. Pat. No. 5,688,819. Although the use of theamidation reaction is a convenient way to prepare the amides related tothis invention in many instances, it is described herein to demonstratethat the preparation of compounds related to this invention can becarried out by methods well known in the art and it is not meant tolimit the scope of the claims in any way.

In other embodiments of particular interest herein the prostaglandin isprostaglandin F_(2α) and the amine is dopamine. In other embodiments ofparticular interest herein the prostaglandin is prostaglandin F_(2α) andthe amine is diacetyl dopamine. In other embodiments of particularinterest herein the prostaglandin is prostaglandin F_(2α) and the amineis serotonin. In other embodiments of particular interest herein theprostaglandin is prostaglandin F_(2α) and the amine is epinephrine.

Another embodiment relates to a compound comprising

or a salt, ester, or prodrug thereof,whereinsaid compound is not naturally occurring;the hatched wedge indicates an α configuration and the solid wedgeindicates a β configuration;the dashed lines indicate the presence or absence of a double bond;A and B are both CHOH, or A is CHOH and B is C═O, or B is CHOH and A isC═O;R¹ is phenyl, indolyl, or monohydroxy or dihydroxy derivatives of phenylor indolyl;

R² is OH or H;

R³ is n-butyl, n-pentyl, or n-hexyl; cyclohexyl, Ar, or W—Ar;wherein Ar is phenyl, naphthyl, thienyl, furanyl, or benzothienyl, or asubstituted derivative of phenyl, naphthyl, thienyl, furanyl, orbenzothienyl, wherein one or two hydrogen atoms is substituted with ahalogen, methyl, or trifluoromethyl; and

W is N, S, O, or CH₂; and

R⁴ is hydrogen, methyl, ethyl, iso-propyl, or n-propyl.

Of particular interest related to this embodiment are compounds whereinR³ is n-butyl, Ar, or W—Ar, wherein Ar is phenyl, naphthyl, thienyl, orbenzothienyl or a substituted derivative of phenyl, naphthyl, thienyl,or benzothienyl, wherein one or two hydrogen atoms is substituted with ahalogen, methyl, or trifluoromethyl. Of exceptional interest are thosecompounds wherein Ar is phenyl, particularly in the cases that W is O orCH₂.

In certain compounds R³ is n-butyl, Ar, or W—Ar, wherein Ar is phenyl.

In other compounds R³ is n-butyl or W—Ar, wherein W is O or CH₂, and Aris phenyl.

In other embodiments related to the aforementioned compounds, R¹ is3,4-dihydroxyphenyl and R² is OH.

In other embodiments related to the aforementioned compounds, R¹ is3,4-dihydroxyphenyl, R² is OH, and R⁴ is methyl.

In other embodiments related to the aforementioned compounds, R¹ is3,4-dihydroxyphenyl, R² is H, and R⁴ is hydrogen.

In other embodiments related to the aforementioned compounds, R¹ is5-hydroxyindolyl, R² is H, and R⁴ is hydrogen.

The following compounds are also of interest

where R¹, R², and R⁴ are the moieties previously described.

The following compounds 1-3 are also useful for the purposes describedherein:

Acetic acid2-acetoxy-5-(2-{(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((E)-(S)-3-hydroxy-oct-1-enyl)-cyclopenyl]-hept-5-enoylamino}-ethyl)-phenylester

(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((E)-(S)-3-hydroxy-oct-1-enyl)-cyclopentyl]-hept-5-enoicacid [2-(3,4-dihydroxy-phenyl)-ethyl]-amide

(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((E)-(S)-3-hydroxy-oct-1-enyl)-cyclopentyl]-hept-5-enoicacid [2-(5-hydroxy-1H-indol-3-yl)-ethyl]-amide

Other compounds contemplated which relate to the embodiments disclosedherein are shown below.

These compounds may be prepared in a manner analogous to those shown inthe Examples provided herein.

In one embodiment, the composition comprises an amide wherein theprostaglandin is prostaglandin F_(2α) or an analog thereof.

In another embodiment, the composition comprises an amide wherein theprostaglandin is prostaglandin E₂ or an analog thereof.

In another embodiment, the composition comprises an amide wherein theprostaglandin comprises from 0 to 2 double covalent bonds connecting twocarbon atoms.

In another embodiment, the composition comprises an amide wherein theprostaglandin comprises two double covalent bonds connecting two carbonatoms.

In another embodiment, the composition comprises an amide wherein theprostaglandin comprises from 1 to 3 heteroatoms, wherein saidheteroatoms comprise S or O, said heteroatoms replacing carbon atomswhich are present in prostaglandin E₂, prostaglandin F₂, orprostaglandin D₂.

In another embodiment, the composition comprises an amide wherein theprostaglandin comprises a moiety which replaces from 2 to 5 carbon atomson the terminal end of a ω chain of a natural prostaglandin, said moietycomprising phenyl, naphthyl, benzothienyl, furanyl, or thienyl.

In another embodiment, the composition comprises an amide wherein thebiogenic amine is tropicamide, or is an analog, a pharmaceuticallyacceptable salt, or a prodrug thereof.

In another embodiment, the composition comprises an amide wherein thebiogenic amine is epinephrine, or is an analog, a pharmaceuticallyacceptable salt, or a prodrug thereof.

In another embodiment, the composition comprises an amide wherein thebiogenic amine is isoprotenenol, or is an analog, a pharmaceuticallyacceptable salt, or a prodrug thereof.

In another embodiment, the composition comprises an amide wherein thebiogenic amine is dopamine, or is an analog, a pharmaceuticallyacceptable salt, or a prodrug thereof.

In another embodiment, the composition comprises an amide wherein thebiogenic amine is phentolamine, or is an analog, a pharmaceuticallyacceptable salt, or a prodrug thereof.

In another embodiment, the composition comprises an amide wherein thebiogenic amine is timolol, or is an analog, a pharmaceuticallyacceptable salt, or a prodrug thereof.

In another embodiment, the composition comprises an amide wherein thebiogenic amine is trancylpromine, or is an analog, a pharmaceuticallyacceptable salt, or a prodrug thereof.

In another embodiment, the composition comprises an amide wherein thebiogenic amine is histamine, or is an analog, a pharmaceuticallyacceptable salt, or a prodrug thereof.

In another embodiment, the composition comprises an amide wherein thebiogenic amine is dimaprit, or is an analog, a pharmaceuticallyacceptable salt, or a prodrug thereof.

In another embodiment, the composition comprises an amide wherein thebiogenic amine is thyroxine, or is an analog, a pharmaceuticallyacceptable salt, or a prodrug thereof.

In another embodiment, the composition comprises an amide wherein thebiogenic amine is serotonin, or is an analog, a pharmaceuticallyacceptable salt, or a prodrug thereof.

One embodiment is an ophthalmic composition comprising a therapeuticallyactive agent or a prodrug thereof,

said therapeutically active agent comprising an amide functional group,whereinselective hydrolysis of said amide functional group of thetherapeutically active agent produces:a compound having agonist activity at a prostaglandin receptor anda compound selected from the group consisting of cholinomimetics,antimuscarinics, adrenergics, dopaminergics, α-adrenoreceptorantagonists, β-adrenergic antagonists, monoamine oxidase inhibitors,histaminergics, serotonergics, and thyroid drugs.

In another composition, selective hydrolysis of said amide functionalgroup produces a compound selected from the group consisting ofadrenergics, dopaminergics, and serotonergics.

In another composition, selective hydrolysis of said amide functionalgroup produces a compound selected from the group consisting ofepinephrine, dopamine, and serotonin, or an analog, a pharmaceuticallyacceptable salt, or a prodrug thereof.

In another composition, said prostaglandin receptor is selected from thegroup consisting of an FP receptor, and EP₁ receptor, an EP₂ receptor,an EP₄ receptor, a DP receptor, and combinations thereof.

In another composition, said compound having agonist activity at aprostaglandin receptor is prostaglandin E, prostaglandin E,prostaglandin F, prostaglandin F, or prostaglandin D₂.

In another composition, said compound having agonist activity at aprostaglandin receptor is prostaglandin F_(2α).

In another composition, selective hydrolysis of said amide functionalgroup produces epinephrine, dopamine, or serotonin.

In another composition, the therapeutically active agent or said prodrugthereof is selected from the group consisting of

-   (Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((E)-(S)-3-hydroxy-oct-1-enyl)-cyclopentyl]-hept-5-enoic    acid [2-(5-hydroxy-1H-indol-3-yl)-ethyl]-amide;-   Acetic acid    2-acetoxy-5-(2-{(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((E)-(S)-3-hydroxy-oct-1-enyl)-cyclopenyl]-hept-5-enoylamino}-ethyl)-phenyl    ester; and-   (Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((E)-(S)-3-hydroxy-oct-1-enyl)-cyclopentyl]-hept-5-enoic    acid [2-(3,4-dihydroxy-phenyl)-ethyl]-amide.

Pharmaceutical compositions may be prepared by combining atherapeutically effective amount of at least one compound disclosedherein, or a pharmaceutically acceptable acid addition salt thereof, asan active ingredient, with conventional ophthalmically acceptablepharmaceutical excipients, and by preparation of unit dosage formssuitable for topical ocular use. The therapeutically efficient amounttypically is between about 0.0001 and about 5% (w/v), preferably about0.001 to about 1.0% (w/v) in liquid formulations.

For ophthalmic application, it is useful for solutions to be preparedusing a physiological saline solution as a major vehicle. In many cases,it is desirable for the pH of such ophthalmic solutions to be maintainedbetween 6.5 and 7.2 with an appropriate buffer system. The formulationsmay also contain conventional, pharmaceutically acceptablepreservatives, stabilizers and surfactants.

Preservatives that may be used in the pharmaceutical compositionsdisclosed herein include, but are not limited to, benzalkonium chloride,chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuricnitrate. A useful surfactant is, for example, Tween 80. Likewise,various vehicles may be used in the ophthalmic preparations of thepresent invention. These vehicles include, but are not limited to,polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers,carboxymethyl cellulose, hydroxyethyl cellulose and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. One useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative  0-0.10 vehicle   0-40 tonicity adjustor   1-10 buffer 0.01-10 pHadjustor q.s. pH 4.5-7.5 antioxidant as needed surfactant as neededpurified water as needed to make 100%

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The ophthalmic formulations disclosed herein are conveniently packagedin forms suitable for metered application, such as in containersequipped with a dropper, to facilitate the application to the eye.Containers suitable for dropwise application are usually made ofsuitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the appended claims.

Example 1 Protection of prostaglandin F_(2α)

A solution of prostaglandin F_(2α) (3.73 g, 10.5 mmol), iodomethane (2.6mL, 42.0 mmol), and 1,8-diazobicyclo[5.4.0] undec-7-ene (3.1 mL, 21.0mmol) in acetone (42 mL) was stirred at 23° C. for 24 hours. Thereaction was concentrated in vacuo and the residue was diluted withethyl acetate and washed with HCl (1 N), saturated sodium bicarbonate,and brine. The organic portion was then dissolved in CH₂Cl₂ (42 mL) withpyridinium p-toluenesulfonate (264 mg, 1.05 mol) and3,4-dihydro-2H-pyran (5.7 mL, 63.0 mmol), and stirred for 12 hours atroom temperature. The reaction was diluted with ethyl acetate and washedwith HCl (1 N), saturated sodium bicarbonate, and brine. The organicportion was dried (MgSO₄), filtered and concentrated in vacuo. Flashcolumn chromatography (4:1 hexane:ethyl acetate) gave the protectedprostaglandin F_(2α) (5.8 g, 89%).

Example 2

A solution of the protected prostaglandin F_(2α) (311 mg, 0.513 mmol) inCH₂Cl₂ (4.5 mL) was treated with triethylamine (290 μL, 2.06 mmol) withstirring and cooled to 0° C. Ethylchloroformate (180 μL, 1.28 mmol) wasthen added and after 15 minutes the reaction was warmed to roomtemperature. Dopamine hydrochloride (487 mg, 2.57 mmol) was added andstirred for 16 hours. The reaction was then diluted with ethyl acetateand washed with HCl (1 N), saturated sodium bicarbonate, and brine. Theorganic portion was dried (MgSO₄), filtered and concentrated in vacuo.The residue was diluted with CH₂Cl₂ (7.5 mL), cooled to 0° C., andtriethylamine (0.34 mL, 3.08 mmol) was added. 4-Dimethylaminopyridine(DMAP) was added (20 mg) followed by acetic anhydride (0.14 mL, 1.58mmol). The reaction was stirred for 16 h, diluted with ethyl acetate,and washed with HCl (1 N), saturated sodium bicarbonate, and brine. Theorganic portion was dried (MgSO₄), filtered and concentrated in vacuo.Flash column chromatography (silica gel, 1:1 hexane:ethyl acetate) gavethe tetrahydropyran (THP) protected diacetate.

The diacetate was diluted with methanol (4.5 mL) and PPTs (50 mg) wasadded and stirred for 16 hours. The solvent was then removed in vacuo,and the residue was diluted with ethyl acetate and washed with HCl (1N), saturated sodium bicarbonate, and brine. The organic portion wasdried (MgSO₄), filtered and concentrated in vacuo. Flash columnchromatography (silica gel, 19:1 ethyl acetate:methanol) gave aceticacid2-acetoxy-5-(2-{(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((E)-(S)-3-hydroxy-oct-1-enyl)-cyclopenyl]-hept-5-enoylamino}-ethyl)-phenylester (Compound 1) (87 mg, 30%).

Example 3

A mixture of acetic acid2-acetoxy-5-(2-{(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((E)-(S)-3-hydroxy-oct-1-enyl)-cyclopenyl]-hept-5-enoylamino}-ethyl)-phenylester (0.57 mg, 0.099 mmol) and aqueous lithium hydroxide (0.5N, 0.8 mL,0.397 mmol) in tetrahydrofuran (THF) (1.6 mL) was stirred for 16 h. Thereaction was diluted with ethyl acetate and acidified with 1 N HCl. Theorganic portion was separated and washed twice with brine, dried(MgSO₄), filtered, and concentrated in vacuo. Flash columnchromatography (silica gel, 19:1 ethyl acetate:methanol) gave(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((E)-(S)-3-hydroxy-oct-1-enyl)-cyclopentyl]-hept-5-enoicacid [2-(3,4-dihydroxy-phenyl)-ethyl]-amide (Compound 2) (7.5 mg, 15%).

Example 4

A solution of the protected prostaglandin F_(2α) (500 mg, 0.825 mmol) inCH₂Cl₂ (4.5 mL) was treated with triethylamine (290 μL, 2.06 mmol) withstirring and cooled to 0° C. Ethylchloroformate (87 μL, 0.907 mmol) wasthen added and after 15 minutes the reaction was warmed to roomtemperature. Serotonin hydrochloride (211 mg, 0.99 mmol) was added andstirred for 16 hours. The reaction was then diluted with ethyl acetateand washed with HCl (1 N), saturated sodium bicarbonate, and brine. Theorganic portion was dried (MgSO₄), filtered and concentrated in vacuo.The residue was diluted with methanol and pyridinium p-toluenesulfonate(PPTs) (100 mg) was added and the solution was stirred for 24 hours. Thesolvent was then removed in vacuo, and the residue was diluted withethyl acetate and washed with HCl (1 N), saturated sodium bicarbonate,and brine. The organic portion was dried (MgSO₄), filtered andconcentrated in vacuo. Flash column chromatography (silica gel, 19:1ethyl acetate:methanol) gave(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((E)-(S)-3-hydroxy-oct-1-enyl)-cyclopentyl]-hept-5-enoicacid [2-(5-hydroxy-1H-indol-3-yl)-ethyl]-amide (Compound 3) (287 mg,68%).

Example 5

Intraocular pressure studies were carried out for compounds 1-3 bypneumatonometry in dogs (Beagle) of both sexes (10-15 kg). The animalsremained conscious throughout the study and were gently restrained byhand. Drugs were administered topically to one eye as a 25 μL volumedrop comprising 0.03% drug, 0.1% polysorbate 80:10 mM TRIS, the othereye received 0.1% polysorbate 80:10 mM TRIS. Proparacaine (0.1%) wasused for corneal anesthesia during tonometry. Intraocular pressure wasdetermined just before drug administration and at 2, 4 and 6 hoursthereafter on each day of the 5 day study. Results are presented in thetable below, which demonstrates that the compound disclosed herein areuseful in decreasing intraocular pressure. Drug was administeredimmediately after the first IOP reading.

Change in Intraocular Pressure (IOP) Compound 0 hrs 2 hrs 4 hrs 6 hrs 24hrs 1 0 −4.4** −3.4** −3.1** −1.4* 2 0 −3.8* −3.2** −3.2** −1.1* 3 0−3.2* −5.8* −7.6** −2.2 *p < 0.05, **p < 0.01, according to Student'spaired t test

What is claimed is:
 1. A composition comprising an amide related to a. aprostaglandin; and b. a biogenic amine.
 2. The composition of claim 1wherein the prostaglandin is a natural prostaglandin selected from thegroup consisting of prostaglandin E, prostaglandin E₂, prostaglandin F,prostaglandin F_(2α), and prostaglandin D₂, or is an analog thereof. 3.The composition of claim 1 wherein the biogenic amine is selected fromthe group consisting of cholinomimetics, antimuscarinics, adrenergics,dopaminergics, α-adrenoreceptor antagonists, β-adrenergic antagonists,monoamine oxidase inhibitors, histaminergics, serotonergics, and thyroiddrugs.
 4. The composition of claim 1 wherein the biogenic amine isselected from the group consisting of tropicamide, epinephrine,isoprotenenol, dopamine, phentolamine, timolol, trancylpromine,histamine, dimaprit, thyroxine, and serotonin, or is an analog, apharmaceutically acceptable salt, or a prodrug thereof.
 5. Thecomposition of claim 1 wherein the prostaglandin is prostaglandin F_(2α)and the amine is dopamine.
 6. The composition of claim 1 wherein theprostaglandin is prostaglandin F_(2α) and the amine is diacetyldopamine.
 7. The composition of claim 1 wherein the prostaglandin isprostaglandin F_(2α) and the amine is serotonin.
 8. A compoundcomprising an amide related to a prostaglandin and a biogenic amine,wherein said compound is not naturally occurring.
 9. The compound ofclaim 8 wherein said biogenic amine is selected from the groupconsisting of cholinomimetics, antimuscarinics, adrenergics,dopaminergics, α-adrenoreceptor antagonists, β-adrenergic antagonists,monoamine oxidase inhibitors, histaminergics, serotonergics, and thyroiddrugs.
 10. The compound of claim 8 wherein the biogenic amine isselected from the group consisting of tropicamide, epinephrine,isoprotenenol, dopamine, phentolamine, timolol, trancylpromine,histamine, dimaprit, thyroxine, and serotonin, or is an analog, apharmaceutically acceptable salt, or a prodrug thereof.
 11. A compoundof claim 8 comprising

or a salt, ester, or prodrug thereof, wherein said compound is notnaturally occurring; the hatched wedge indicates an α configuration andthe solid wedge indicates a β configuration; the dashed lines indicatethe presence or absence of a double bond; A and B are both CHOH, or A isCHOH and B is C═O, or B is CHOH and A is C═O; R¹ is phenyl, indolyl, ormonohydroxy or dihydroxy derivatives of phenyl or indolyl; R² is OH orH; R³ is n-butyl, n-pentyl, or n-hexyl; cyclohexyl, Ar, or W—Ar; whereinAr is phenyl, naphthyl, thienyl, furanyl, or benzothienyl, or asubstituted derivative of phenyl, naphthyl, thienyl, furanyl, orbenzothienyl, wherein one or two hydrogen atoms is substituted with ahalogen, methyl, or trifluoromethyl; and W is N, S, O, or CH₂; and R⁴ ishydrogen, methyl, ethyl, iso-propyl, or n-propyl. The compound of claim31 wherein R³ is n-butyl, Ar, or W—Ar, wherein Ar is phenyl, naphthyl,thienyl, or benzothienyl or a substituted derivative of phenyl,naphthyl, thienyl, or benzothienyl, wherein one or two hydrogen atoms issubstituted with a halogen, methyl, or trifluoromethyl.
 12. The compoundof claim 8 comprising


13. The compound of claim 8 comprising


14. The compound of claim 8 comprising


15. A method of treating glaucoma comprising administering to a mammalsuffering from glaucoma an effective amount of a therapeutically activeagent or a pharmaceutically acceptable salt or a prodrug thereof, saidtherapeutically active agent consisting of a prostaglandin and abiogenic amine having 5 or more carbon atoms coupled by an amide bond.16. The method of claim 15 wherein said biogenic amine is selected fromthe group consisting of cholinomimetics, antimuscarinics, adrenergics,dopaminergics, α-adrenoreceptor antagonists, β-adrenergic antagonists,monoamine oxidase inhibitors, histaminergics, serotonergics, and thyroiddrugs.
 17. The method of claim 15 wherein said biogenic amine comprisesa 2-aryl-1-ethylamine.
 18. The method of claim 17 wherein the2-aryl-1-ethylamine comprises from 1 to 3 hydroxy or acetyloxy moieties.19. The method of claim 15 wherein said prostaglandin is an FP-relatedprostaglandin.
 20. The method of claim 15 wherein said prostaglandin isan EP-related prostaglandin.